This invention relates to the treatment of neurodegenerative diseases.
In human and nonhuman primates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical, neuropathologic changes analogous to those observed in idiopathic Parkinson's disease. The neurotoxic effects of MPTP are thought to be initiated by 1-methyl-4-phenylpyridinium (MPP+), which is a metabolite formed by the monoamine oxidase B-mediated (MAO-B) oxidation of MPTP (for review, see Tipton and Singer (1993) J. Neurochem. 61:1191-1206). MPP+ is selectively taken up by high-affinity dopamine and noradrenaline uptake systems and is subsequently accumulated within mitochondria of dopaminergic neurons. There it disrupts oxidative phosphorylation by inhibiting complex I of the mitochondrial electron transport chain (Gluck et al. (1994) J. Biol. Chem. 269:3167-3174). The interruption of oxidative phosphorylation results in decreased levels of ATP (Chan et al. (1991) J. Neurochem. 57:348-351), which may lead to partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, resulting in excitotoxic neuronal cell death (Beal (1992) Ann. Neurol. 31:119-130). Although excitotoxic neuronal damage has been linked to Ca.sup.2+ influx, the subsequent crucial steps that lead to cell death remain unknown.
The entry of calcium through N-methyl-D-aspartate (NMDA) receptor channels into cells stimulates nitric oxide synthase (NOS) activity by binding to calmodulin, a cofactor for NOS (Bredt and Snyder (1990) Proc. Natl. Acad. Sci. USA 87:682-685). Studies in dissociated cell cultures showed that NOS inhibitors blocked NMDA-induced cell death (Dawson et al. (1991) Proc. Natl. Acad. Sci. USA 88:6368-6371). NO.sup..cndot. may react with superoxide (O.sub.2.sup..cndot.) to generate peroxynitrite (Beckman et al. (1990) Proc. Natl. Acad. Sci. USA 87:1621-1624). Peroxynitrite has been identified as a potent oxidant (Beckman et al. (1992) Arch. Biochem. Biophys. 298:438-445; Ischiropoulos et al. (1992) Arch. Biochem. Biophys. 298:431-437), mediating the nitration of tyrosine and producing hydroxyl radicals (Beckman et al. (1990) supra; Crow et al. (1994) Free Radic. Biol. Med. 16:331-338; van der Vliet et al. (1994) FEBS Lett. 339:89-92). NOS has been implicated as having a role in focal ischemia (Huang et al. (1994) Science 265:1883-1885).
Recently, improved inhibitors of NOS have been described. 7-nitroindazole (7-NI) has been reported to be a potent and selective inhibitor of neuronal NOS in vitro and in vivo (Babbedge et al., (1993) Br. J. Pharmacol. 110:225-228; Moore et al. (1993) Br. J. Pharmacol. 110:219-224). Although in vitro studies suggest that 7-NI inhibits both endothelial and neuronal NOS, in vivo studies showed no effect on blood pressure and no effects on endothelium-dependent blood vessel relaxation and acetylcholine-induced vasodepressor effects (Babbedge et al. (1993) supra; Moore et al. (1993) supra, Wolff and Gribin (1994) Arch. Biochem. Biophys. 311:300-306). 7-NI has been shown to be efficacious against focal ischemic lesions in vivo (Yoshida et al. (1994) J. Cereb. Blood Flow Metab. 14:924-929).